Comparison of diagnostic genetic testing and clinical scoring results for familial chylomicronemia syndrome (FCS) in the 66-patient Balance study

Abstract

Funding

This study was sponsored by Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. The first draft was written by Mary Beth DeYoung, PhD of Ionis Pharmaceuticals, Inc., Carlsbad, CA, USA. Editorial support was provided by Red Nucleus and funded by Ionis Pharmaceu

Background/Synopsis

Familial chylomicronemia syndrome (FCS), a rare, pancreatitis-associated genetic disorder, is commonly misdiagnosed. An FDA-approved treatment for FCS in the United States increases the urgency for accurate, reliable and timely diagnosis. While potentially definitive, FCS diagnosis based on genetic testing may not be accessible or conclusive. Clinical scoring systems have been devised as a diagnostic alternative. For instance, the North American (NA) FCS scoring system was devised using the RAND/UCLA modified Delphi process as a practical, rapid, validated tool to diagnose FCS (Hegele et al, J Clin Lipidol 2024). The detection sensitivity of a score ≥ 45 is 89% and the specificity is 97%.

Objective/Purpose

To evaluate the sensitivity of the NAFCS scoring system in the 66 genetically identified FCS patients enrolled in Balance, a phase 3 study on the efficacy and safety of olezarsen. Olezarsen is an APOC3 directed antisense oligonucleotide approved by the United States FDA as an adjunct to diet to reduce triglycerides in adults with FCS.

Methods

NAFCS scores were calculated individually for Balance patients using established methodology. Scoring parameters include age of severe hypertriglyceridemia (sHTG) onset; body-mass index (BMI) < 25 kg/m²; history of pancreatitis; secondary factors contributing to sHTG; and laboratory values (TG > 880 mg/dL, TG/TC > 8.00, and ApoB-100 < 1.00 g/L). A NAFCS score > 45 and ≥ 60 identified patients with “likely” or “definite” genetic FCS, respectively. Genetic testing procedures and results are described in the Balance publication (PMID: 38587247).

Results

The mean (SD) NAFCS score overall was 66 (14); range 33 to 93. Of 66 patients, 63 (95%) and 49 (74%) had NAFCS scores ≥ 45 and ≥ 60, respectively. Variability was found in some key attributes (Table). A high proportion (> 95%) of FCS patients had TG > 880 mg/dL and ApoB-100 < 1.00 g/L at screening, nearly 80% had no secondary risk factors for sHTG, and ∼70% had a history of acute pancreatitis. More than half of patients had BMI < 25 kg/m². Although the sample was small, patients with NAFCS scores < 45 in Balance appeared less likely to have pathogenic LPL variants than patients with scores ≥ 45 (1/3 [33%] versus 54/63 [86%], respectively).

Conclusions

The NAFCS score incorporates laboratory parameters, particularly low ApoB-100, which was found in nearly all FCS patients in Balance. In Balance, the NAFCS score showed a sensitivity of 74% for the highly selective score of ≥ 60 and 95% for ≥ 45. These results suggest that the NAFCS scoring system might simplify diagnosis of FCS, supporting earlier access to treatment.